Triethylamine → cyclopropanecarboxylic acid {2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide

HRID 1784994노트

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HRID 1784994 반응식
[F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH2:16])[CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][C:5]=1[O:17][CH2:18][CH3:19].CCN(CC)CC.C[O:29][C:30](=O)[C:31]1[C:36]([NH:37][C:38]([CH:40]2[CH2:42][CH2:41]2)=[O:39])=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:43]Br>CN(C=O)C>[F:20][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([N:16]2[C:30](=[O:29])[C:31]3[C:32](=[CH:33][CH:34]=[CH:35][C:36]=3[NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[CH2:43]2)[CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][C:5]=1[O:17][CH2:18][CH3:19]

참가 물질

5

반응물 3

HCID 8471TriethylamineHCID 588000791-(4-Difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethylamineHCID 669203212-Bromomethyl-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester

생성물 1

HCID 10481374cyclopropanecarboxylic acid {2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide수율 30%

시약·촉매·용매 1

HCID 6228Dimethylformamide용매

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온도
90 °C

실험 절차

To the DMF solution (20 ml) of 1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethylamine (0.80 g, 2.7 mmol) was added Et3N (1.6 ml, 12 mmol) followed by 2-bromomethyl-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (1.0 g, 3.2 mmol). The mixture was heated at 90° C. for 12 hours then cooled to room temperature. The mixture was extracted with EtOAc (50 ml) and water (50 ml). The organic layer was washed with water (50 ml) and brine (50 ml), dried over Na2SO4 and concentrated in vacuo. The resulted oil was purified by silica gel chromatography to give cyclopropanecarboxylic acid {2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (0.35 g, 30%): mp 115-117° C.; 1H NMR (CDCl3) δ 0.83-0.92 (m, 2H, c-CH2), 1.09-1.13 (m, 2H, c-CH2), 1.45 (t, J=7.0 Hz, 3H, CH3), 1.66-1.70 (m, 1H, c-CH), 2.98 (s, 3H, SO2CH3), 3.64 (dd, J=3.8, 14 Hz, 1H, CH2), 4.10 (q, J=6.8 Hz, 2H, OCH2), 4.33 (dd, J=10, 14 Hz, 1H, CH2), 4.37 (dd, J=5, 50 Hz, 2H, CH2N), 5.69-5.74 (m, 1H, NCH), 6.57 (t, JH-F=75 Hz, 1H, CF2H), 6.94-7.04 (m, 3H, Ar), 7.18 (d, J=7.5 Hz, 1H, Ar), 7.47 (t, J=7.5 Hz, 1H, Ar), 8.45 (d, J=8.5 Hz, 1H, Ar), 10.42 (s, 1H, NH); 13C NMR (CDCl3) δ 9.06, 15.3, 16.9, 42.4, 49.0, 52.5, 56.3, 65.6, 112.4, 113.9, 116.6, 117.5, 117.6, 118.7, 119.9, 120.7, 123.8, 134.5, 136.5, 138.9, 141.1, 141.9, 151.9, 170.9, 173.4; Anal Calcd for C24H26F2N2O6S: C, 56.68; H, 5.15; N, 5.51. Found: C, 56.72; H, 5.15; N, 5.38.

후처리

  1. temperaturethen cooled to room temperature
  2. extractionThe mixture was extracted with EtOAc (50 ml) and water (50 ml)
  3. washThe organic layer was washed with water (50 ml) and brine (50 ml)
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated in vacuo
  6. customThe resulted oil was purified by silica gel chromatography

출처 및 근거

ORD 기록
ord-369d00d1b1a247dd9166d078e2cebea8
출처 데이터셋
uspto-grants-2009_03
특허 번호
US07504427B2

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